Nicotinic receptors and lurasidone-mediated reversal of phencyclidine-induced deficit in novel object recognition

Abstract Background Enhancement of cholinergic function via nicotinic acetylcholine (ACh) receptor (nAChR) agonism is a potential approach for the treatment of cognitive impairment associated with schizophrenia (CIAS). Some atypical antipsychotic drugs (AAPDs) enhance ACh release in rodent brain, indirectly stimulating these receptors. Here, we elucidate which nAChR subtypes mediate novel object recognition (NOR) in normal rats and contribute to the ability of the AAPD, lurasidone, to improve the NOR deficit in sub-chronic (sc) phencyclidine (PCP)-treated rats, a model for CIAS. Methods The ability of lurasidone and nAChR ligands to reverse the scPCP-induced deficit in NOR was assessed in female, Long-Evans rats. Results The broad acting nAChR antagonist, mecamylamine (MEC), induced a NOR deficit in normal rats. The NOR deficit secondary to scPCP was reversed by either selective α 4 β 2 * nAChR agonism (A-85380) or α 7 nAChRs agonism (PNU-282987); these effects were blocked by DHβE and MLA, selective antagonists of α 4 β 2 * and α 7 nAChR, respectively. The ability of lurasidone to reverse the scPCP-induced NOR deficit was blocked by MEC, but not MLA or DHβE. However, sub-effective doses (SED) of either A-85380 or PNU-282987 potentiated the ability of SED lurasidone to reverse the scPCP-induced NOR deficit. Conclusions These results identify both α 4 β 2 * and α 7 nAChRs as candidates for enhancing the ability of lurasidone and other AAPDs, which increase the release of ACh, to improve CIAS.